rs1800014

chr20-4699875-G-Achr20-4699875-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000311.5(PRNP):c.655G>A(p.Glu219Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,613,590 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (180 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 1.04

Genes affected

PRNP (HGNC:9449): (prion protein (Kanno blood group)) The protein encoded by this gene is a membrane glycosylphosphatidylinositol-anchored glycoprotein that tends to aggregate into rod-like structures. The encoded protein contains a highly unstable region of five tandem octapeptide repeats. This gene is found on chromosome 20, approximately 20 kbp upstream of a gene which encodes a biochemically and structurally similar protein to the one encoded by this gene. Mutations in the repeat region as well as elsewhere in this gene have been associated with Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler disease, Huntington disease-like 1, and kuru. An overlapping open reading frame has been found for this gene that encodes a smaller, structurally unrelated protein, AltPrp. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000311.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.00404042).
• BP6: Variant 20-4699875-G-A is Benign according to our data. Variant chr20-4699875-G-A is described in ClinVar as [Benign]. Clinvar id is 13409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699875-G-A is described in Lovd as [Likely_benign]. Variant chr20-4699875-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00308 (468/151736) while in subpopulation SAS AF= 0.0552 (264/4786). AF 95% confidence interval is 0.0497. There are 18 homozygotes in gnomad4. There are 311 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.655G>A	p.Glu219Lys	missense_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.655G>A	p.Glu219Lys	missense_variant	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.655G>A	p.Glu219Lys	missense_variant	2/2	1		P1
PRNP	ENST00000430350.2	c.655G>A	p.Glu219Lys	missense_variant	2/2	1		P1
PRNP	ENST00000457586.2	c.655G>A	p.Glu219Lys	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 468 AN: 151618 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0332

Gnomad SAS AF: 0.0553

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00802 AC: 2016 AN: 251398 Hom.: 48 AF XY: 0.00934 AC XY: 1269 AN XY: 135858

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0356

Gnomad SAS exome AF: 0.0413

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00410 AC: 5987 AN: 1461854 Hom.: 180 Cov.: 32 AF XY: 0.00515 AC XY: 3745 AN XY: 727228

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0500

Gnomad4 SAS exome AF: 0.0415

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00308 AC: 468 AN: 151736 Hom.: 18 Cov.: 32 AF XY: 0.00420 AC XY: 311 AN XY: 74124

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000526

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0330

Gnomad4 SAS AF: 0.0552

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00220 Hom.: 8

Bravo AF: 0.00211

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00875 AC: 1062

Asia WGS AF: 0.0450 AC: 155 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2022	- -

Protection against Creutzfeldt-Jakob disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Feb 01, 2012

- -

Inherited prion disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Huntington disease-like 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.45	N
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.0	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.035	D;D;D
Sift4G	Benign	0.090	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.17
MVP		1.0
MPC		0.55
ClinPred		0.0090	T
GERP RS		3.1
Varity_R		0.21
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800014; hg19: chr20-4680521; COSMIC: COSV65173750; COSMIC: COSV65173750;